Distinct normal cells-of-origin may underlie the phenotypic heterogeneity of human breast carcinomas. Perturbations of the normal epigenetic programs of various cells-of-origin may play roles in tumor initiation, metastatic progression, and resistance to therapies. To begin investigating these issues, we characterized. the comprehensive DMA methylation and gene expression profiles of differentiated CD24+ luminal epithelial and CD44+ stem cell-like cells from normal and neoplastic human breast tissue. We identified cell-typespecific DMA methylation patterns that correlated strongly with the histopathological subtypes and clinical outcome of human breast carcinomas. The relatedness of normal and neoplastic DNA methylation patterns was dependent on breast tumor subtypes. Based on these observations, we hypothesize that genes associated with distinct chromatin patterns in mammary epithelial stem and differentiated cells play key roles in determining stem-cell function and lineage-specific differentiation, and that perturbation of these patterns alters cell fate. Furthermore, we hypothesize that normal cell type-specific chromatin patterns are perturbed in breast tumors and that they vary depending on breast tumor types. We propose three specific aims to test these hypotheses.
Aim 1 : To characterize the histone methylation profiles of human mammary epithelial stem and differentiated cells isolated from normal human breast tissue. We will use ChIP (chromatin immunoprecipitation) and quantitative PCR followed by ChlPSeq genome-wide studies.
Aim 2 : To characterize the histone methylation profiles of stem cell-like and more differentiated breast cancer cells isolated from different breast tumor subtypes. We will analyze the histone methylation of stem cell-like and more differentiated cells-from different stage tumors of several subtypes (e.g., luminal, HER2+, and basallike tumors) as described in Aim 1.
Aim 3. To determine the functional relevance of the cell type-specific epigenetic patterns. To determine the functional relevance of cell type-specific histone methylation patterns, we will analyze the consequences of perturbing these patterns on cell fate and differentiation both in normal and neoplastic human breast tissue.

Public Health Relevance

Breast cancer is a heterogeneous disease. Variability among and within tumors plays key roles in determining clinical outcome;yet our understanding of what causes this heterogeneity is rudimentary. The proposed project will investigate if cell type-specific differentiation programs and their perturbation may explain breast tumor heterogeneity and if targeting these programs may influence clinical outcome.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Whitehead Institute for Biomedical Research
United States
Zip Code
Zhang, Jinfang; Xu, Kai; Liu, Pengda et al. (2016) Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt. Mol Cell 62:929-42
Spiegel, Asaf; Brooks, Mary W; Houshyar, Samin et al. (2016) Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells. Cancer Discov 6:630-49
Shu, Shaokun; Lin, Charles Y; He, Housheng Hansen et al. (2016) Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529:413-7
Hydbring, Per; Malumbres, Marcos; Sicinski, Piotr (2016) Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 17:280-92
De Cock, Jasmine M; Shibue, Tsukasa; Dongre, Anushka et al. (2016) Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency. Cancer Res 76:6778-6784
Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81
Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609
Huh, Sung Jin; Oh, Hannah; Peterson, Michael A et al. (2016) The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women. Cancer Res 76:1926-34
Wang, Hua; Bierie, Brian; Li, Andrew G et al. (2016) BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells. Mol Cell 63:277-92
Goel, Shom; Wang, Qi; Watt, April C et al. (2016) Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 29:255-69

Showing the most recent 10 out of 114 publications